Enhancement of the cytotoxicity of cytosine arabinoside by interleukin-3.

We have evaluated the feasibility of enhancing the cytotoxic effect of cytosine arabinoside (ara-C) on acute myeloid leukemia (AML) cells by increasing the proliferative activity with hematopoietic growth factors. Leukemic cells from 8 persons with AML were tested. Preincubation with interleukin (IL)-3 (5 U/ml) for 3 days increased DNA synthesis as measured by tritiated thymidine incorporation and Ki67 expression in cells from 7 out of 8 persons with AML. Leukemic cells preincubated with IL-1 (10 U/ml) or IL-3 (5 U/ml) were subsequently exposed to ara-C (3 micrograms/ml) for the final 24 h and the activity of ara-C against clonogenic acute myeloid leukemia cells was evaluated in terms of the inhibition of colony formation in semisolid media. The exposure to ara-C inhibits the proliferation of a higher proportion of clonogenic cells in culture pretreated with IL-3 than in control or cells pretreated with IL-1. The enhanced cytotoxic effect of ara-C in the cells pretreated with IL-3 correlated with increased formation of intracellular ara-CTP. IL-3-induced recruitment of quiescent blasts into the proliferative compartment will lead to increased formation of ara-CTP in the cells, which would result in an enhanced leukemia cell kill.